The penetration of the blood-brain barrier (BBB) by neurologically active peptides has remained an enigmatic problem for many decades. Studies have shown that glycosylation of small peptides (enkephalins) leads to glycopeptides that are more stable, and which penetrate the BBB in pharmacologically useful amounts. Mechanistic studies have shown that endocytosis at the endothelial layer of the brain capillaries is responsible for transport. Recent studies indicate that much larger peptides (endorphins) are capable of adopting helical conformations in the presence of membranes, and are also transported across the BBB. This proposal seeks to explore and exploit the transport and pharmacology of glycosylated dynorphin and endorphin peptides, and to evaluate them as candidates for the treatment of chronic pain. A unique group of investigators has been assembled in order to bring synthetic organic, biophysical, and pharmacological tools to bear on this problem. Solution and solid phase NMR techniques will examine the effects of glycopeptide adsorption to membrane models, seeking to understand the effects on glycopeptide conformation, as well perturbations of the membrane during adsorption. Data from these studies will be correlated with glycopeptide stability, transport rates, and binding affinities. Finally, behavioral studies in mice will be carried out to test the effects of systematic administration of these drugs in models of inflammatory and neuropathic pain, opioid-mediated side effect (Gl transit, tolerance/dependence, etc.) and anxiety/depression. Based on our previous research and published papers on delta receptors, we predict that some of the compounds will have better efficacy, reduced toxicity and/or improved side effect profiles compared to morphine-like analgesics. More importantly, the central hypothesis (that glycosylation strategies can be applied to larger peptides to increase CNS bioavailability) will be rigorously tested using a multidisciplinary approach. If the hypothesis is supported, the technology may lead to a sea-changing platform technology on which to base the clinical development of diverse pharmaceuticals based on endogenous neuropeptides.